title: A phase 1, dose-escalation, pharmacokinetic and pharmacodynamic study of BIIB021 administered orally in patients with advanced solid tumors.
abstract: OBJECTIVE
  BIIB021 is the first oral, synthetic, non-geldanamycin-based HSP90 inhibitor that showed activity in preclinical models at low nanomolar concentrations. We performed a phase 1 trial of BIIB021 administered to subjects with advanced solid tumors.
  
  
  METHODS
  Sixty patients received BIIB021 capsules orally on days 1, 4, 8, 11, 15, and 18 of each course in schedule 1, and on days 1, 4, 8, 11, 15, 18, 22, and 25 of each course in schedule 2. The treatment schedules were repeated every 28 days. In addition to determining the MTD, we evaluated pharmacokinetics of BIIB021 and pharmacodynamic effects of BIIB021 [Hsp70, HER2 extracellular domain (HER2-ECD)].
  
  
  RESULTS
  The MTD was 700 mg twice weekly when BIIB021 was dosed for 3 weeks out of each 4-week course. The MTD for continuous dosing regimen was established at 600 mg twice weekly. Gastrointestinal (nausea, vomiting), hot flashes, and neurologic (dizziness) events characterize the safety profile of BIIB021 dosed twice weekly, with events mostly mild or moderate. Plasma exposure to BIIB021 was dose-dependent. Cmax occurred at approximately 90 minutes and t1/2 was approximately 1 hour across dosing cohorts of 25 to 800 mg BIIB021 twice weekly. The biologic activity of BIIB021 was demonstrated in serum, PBMCs, and tumor tissue. Hsp70 levels were increased (>150% from baseline) and serum HER2-ECD was significantly decreased (>15% inhibition from baseline).
  
  
  CONCLUSIONS
  BIIB021 twice weekly, given with or without the 1 of 4-week rest period was tolerated in subjects with advanced solid tumors at doses that are pharmacodynamically active.
authors.affiliation: Authors' Affiliations: Tufts University School of Medicine, Boston, Massachusetts; Institute for Drug Development Cancer Therapy and Research Center, San Antonio, Texas; Institute of Cancer Research, Royal Marsden Hospital, London, United Kingdom; Memorial Sloan-Kettering Cancer Center, New York, New York; University of California San Diego; Biogen Indec, San Diego, California; University of Texas M.D. Anderson Cancer Center, Houston, Texas; and TGen Clinical Research Services at Scottsdale Healthcare, Scottsdale, Arizona.
authors.forename: Muhammad Wasif
authors.initials: MW
authors.lastname: Saif
authors.forename: Chris
authors.initials: C
authors.lastname: Takimoto
authors.forename: Monica
authors.initials: M
authors.lastname: Mita
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
authors.forename: Nicole
authors.initials: N
authors.lastname: Lamanna
authors.forename: Januario
authors.initials: J
authors.lastname: Castro
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Christopher
authors.initials: C
authors.lastname: Stogard
authors.forename: Daniel
authors.initials: D
authors.lastname: Von Hoff
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D001706:Biopsy; D004334:Drug Administration Schedule; D019788:Fluorodeoxyglucose F18; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood / Q000378:metabolism; D042541:Intracellular Space; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood
chemical_list: D000225:Adenine; D000970:Antineoplastic Agents; D019788:Fluorodeoxyglucose F18; D018841:HSP90 Heat-Shock Proteins; D018971:Insulin-Like Growth Factor Binding Protein 2; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; C521963:6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine